19-bisdifluoro-androstanes



United States Patent 3,257,430 19-BlSDIFLUOR0-ANDROSTANES Albert Bowersand James C. Orr, Mexico City, Mexico,

assignors to Syntex CorporatiomPanama, Panama, a

corporation of Panama No Drawing. Filed Sept. 21, 1962, Ser. No. 225,36321 Claims. (CL 260--397.4)

The present invention relates to novel cyclopentanophenanthrenederivatives and to a process for the production thereof.

More particularly, the present invention relates to novel 19,19'difluoroandrostane derivatives.

The novel compounds of the present invention are represented by thefollowing formulae:

In the above formulae R represents hydrogen or a hydr-ocarboncarboxyli'c acyl group of less than 12 carbon atoms; R representshydrogen, lower alkyl, lower alkenyl or lower alkynyl; R representshydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbonatoms; R represents hydrogen, lower alkyl, or a hydrocarbon car'-boxylic acyl group of less than 12 carbon atoms; and Z represents adouble bond or a saturated linkage between C-4 and C-5.

The acyl group are derived from hydrocarbon carboxylic acids containingless than 12 carbon atoms which may be saturated or unsaturated, ofstraight, branched, cyclic-aliphatic chain, aromatic and may besubstituted by functional groups such as hydroxy, alkoxy containing upto 5 carbon atoms, a'cyloxy containing up to 12 carbon atoms, n-itro,amino or halogen. Typical ester groups are the acetate, propionate,enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate,cyclopentylpropionate, aminoacetate and ,B-chloropropionate.

The novel compounds of the present invention represented by the aboveformulae are anabolic-androgenic agents with a favorableanabolic-androgenic ratio. In addition they have anti-estrogenic,anti-gonadotroph'ic, anti fibrillatory and appetite stimulatingproperties. Furthermore, they lower the blood cholesterol level, relievepremenstrual tension, and suppress the output of the pituitary gland.

The compounds represented by the above formulae 3,257,439 Patented June21, 1966 "ice Wherin R is a lower alkynyl group, are also useful infertility control.

The novel compounds of the present invention are prepared by the processillustrated as follows:

FaHC

IV III VII In the above formulae R, R R and R have the same meaning asherein set forth.

The starting compound of the process just outlined which is a diacylateof a A -androstene-3p,17/i-diol-l9-al derivative (I), preferably thediacetate, is obtained in accordance with Bowers U.S. patent applicationSerial No. 201,768, filed June 12, 1962, by treatment of thecorresponding acylate of A -androsten-3fl-ol-l7-one with hypobrornousacid, reaction of the resulting 5a-brorno-6B-o1 with lead tetraacetate,treatment of the resulting acyla-te of the corresponding5a-bromo-6fl,19oXido-androstan-3B-ol- 17-one with zinc in a loweraliphatic alcohol, reaction with dihydropyrane in the presence ofp-toluenesulfonic acid of the resulting 3-acylate of A-androstene-3B,l9-diol-l7- one to give the corresponding-19-tetrahydropyranylether 3-acetate of A-andros-tene-3fi,19-diol-l7-one, reduction of the 17-keto group of thelatter to give the corresponding Uri-alcohols, or treatment of the same17-keto group with a lower (alkyl, alkenyl or alkynyl) magnesium bromideto give the corresponding Ha-hydrocarbon substituted- 17fi-ol,conventional esteri-fication of the free alcohols to give thecorresponding 3,17-diacylates-l9-tetnahydropyranylether of thecorresponding 17OL-SUbStltUted or unsubstituted A-androstene-3p,l7,B,il9-triol, acid hydrolysis of 3 the19-tetrahydropyranyl ether group followed by oxidation with chromiumtrioxide in pyridine to give the desired 3,17-diacylates of thecorresponding.A -androstene- 36,17B-diol-19-al derivative.

In practicing the process outlined above the starting compound (I) istreated with 2 molar equivalents of sulphur tetrafiuoride at 50 C. in asealed vessel for a prolonged period of time of the order of 6 to 14days, preferably for 8 days, to give the diacylate of the corresponding19,19-difluoro-A -androstene-3fi,-17B-diol (II), which, uponconventional saponification in a basic medium affords the corresponding3,8,17B-free diol (II: R =R==H). The Her-substituted 19,19-difluoro-A-androstene-3B,l7B-diol upon treatment under conventional Oppenaurerconditions, affords 19,19-difluoro-A -androstene-3,l7-di0ne which isreducedwith a double metal hydride prefer-ably sodium borohydride togive 19,19-difluoro-A -androstene-3p,17,8-diol which is finally treatedwith 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1 molar equivalent) inan inert solvent such as dioxane at room temperature, for a period oftime of the order of 3 hours, thus affording 19,19-difluoro-A-androstene-17fl-ol-3-one (III: R=R :I-I). In the case of the3fi,17,8-diols with a substituent at C-17oc, the oxidation underOppenaurer conditions gives directly the corresponding .17a-substituted-A -androstene-17,8-01-3-one (III: R=H, R =lower aliphatic residue). Thel9,19-difluoro-A -androstene-175-01- 3-one derivatives (III) are treatedwith an alkali metal such as lithium, in ammonia followed by treatmentwith ammonia chloride to give the corresponding19,19-difluoro-androstene-l7fi ol-3-one compounds (IV).

The latter compounds upon treatment with ethyl formate in the presenceof sodium hydride and in an inert solvent such as benzene for a periodof time of the order 24 hours, at room temperature, yield thecorresponding Z-hydroxymethylene-19,19-difiuoro-androstan 17B ol- 3 onederivatives (V: R =H) which are treated with an excess of a diazoalkane,preferably diazomethane, in ether to give the cor-responding2-alkoxymethylene compounds, preferablyZ-methoxymethylene-l9,19-difluoroandrostane-l7B-ol-3-one compound (V: Rmethyl). The latter derivatives upon reduction with a double metalhydride, preferably sodium borohydri-de followed by acid treatment, forexample with hydrochloric acid yield the corresponding 2formyl-19,19-difluoro-A -androsten-17B- ol compounds (VI). The lastnamed compounds are treated with N,O-bis-(trifluoromethyl)-hydroxylaminein an inert solvent, such as benzene, under anhydrous conditions, for aperiod of time of the order of 4 hours, to give the corresponding2-cyano-19,19-difluoro-A randrosten-17fi-ol derivatives (VII).

The compounds of the present invention having a secondary hydroxylgroup, such as the 3fi-hydroxyl, or the 1713- hy-droxyl of theNot-unsubstituted compounds, or a hydroxymethylene group, areconventionally acylated in pyridine with an acylating agent, such as ananhydride or a chloride of a hydrocarbon carboxylic acid of the typedefined hereinbef-ore, thus affording the corresponding acyl-ates.

The compounds of the present invention having a tertiary hydroxyl group,namely the 17(3-hydroxy1'of the Nor-substituted derivatives, areconventionally esterified in the presence of p-toluenesulfonic acid oranhydrous sodium methoxide with excess of an acylating agent, such asacetic anhydride or caproic anhydride, to give the corpatent applicationSerial No. 201,768 filed June 12, 1962,

in 100 cc. of anhydrous benzene there were added 1 g. of

p-toluenesulfonic acid and 10 cc. of acetic anhydride and the mixturewas allowed to stand for 24 hours at room temperature, poured into iceand water, and the resulting mixture stirred to effect hydrolysis of theexcess anhydride. The benzene layer was separated and washed with 10%sodium carbonate solution and water. Drying, evaporation andcrystallization of the residue from ether-hexane produced the diacetateof 17a-methyl-A androstene-3,8,l7p-diol-19-al.

Following the same procedure there were treated 17avinyl-A-androstene-3fi,l7 B-diol-19-al and 17u-ethynyl A-androstene-3fi,17fl-dio1-19-al (obtained in accordance with theaforesaid Ap-pl.) to produce respectively: 170cvinyl-A-androstene-3/L17fi-diol-19-al diacetate and 1704-- ethynyl-A-androstem-3,8,17fl-diol-l9-al, diacetate.

Example I 500 mg. of the diacetate of A -androstene-35,l7fi-diol- 19 al,obtained in accordance with the aforesaid patent application, weredissolved in 15 cc. of chloroform containing 0.3 cc. of ethanol in astainless steel bomb. The solution was cooled to 70 C., 1 cc. of sulfurtetrafluoride was added, and the tube sealed with a stainless steelstopper. After 8 days at 050 C. the steel bomb was again cooled, opened,and the contents of the tube poured into aqueous sodium carbonate.Extraction with ethyl acetate, washing to neutral with water, drying,and evaporation to dryness gave a non-crystalline sol-id. Chromatographyon alumina gave the diacetate of 19,19- difiuoro-A-androstene-3fi,17,8-diol (Compound No. 1).

Following the same procedure there were treated the diacetate of17u-methyl-M-androstene-36,l7e-diol-19-a1, the diacetate of l7a-vinyl-A-androstene-3fl,17,8-diol-19-al and the diacetate 0f 17a-ethynyl-A-androstenefl,17pdi01-19-al, 'thus affording respectively: the diacetateof 19,19 difluoro 17oz met-hyl-A -androstene-3B,17fl-diol (Cpd. No. 2),the diacetate of l9,l9-difluoro-17a-vinyl- A -androstene-3B,l7/8-diol(Cpd. No. 3) and the diacetate of 19,19 difluoro 170a ethynyl-A-androstene-3B,17,6-

diol (Cpd. No. 4).

' Example 11 A suspension of l g. of l9,19-difluoro-A -androstene-35,17,8-diol diacetate (Cpd. No. 1) in 60 cc. of methanol was treatedwith a solution of 1 g. of potassium carbonate in 6 cc. of water; themixture was boiledunder reflux for 1 hour and then cooled in ice anddiluted with water. The formed precipitate was collected andrecrystallized from acetone-hexane to yield 19,19-difluoro-A-androstene-3 3,-l7;3diol (Cpd. No. 5).

Example III A solution of 0.17 g. of potassium hydroxide in 0.2 cc. ofwater and 2.5 cc. of methanol was added over 30 minutes to a boilingsolution of 1 g. of the diacetate of 19,19- difluoro-17u-methyl-A-androstem-3p,17fi-diol (Cpd. No. 2), in 30 cc. of methanol under anatmosphere of nitrogen. Boiling was continued for a further 2 hours andthe solution was then cooled, neutralized with acetic acid andconcentrated'under reduced pressure. Addition of water, followed bycrystallization of the precipitated solid from acetone-hexane, produced19,19-difluoro-l7a-methyl- A -androstene-3fi,17fl-diol (Cpd. No. 6).

The compounds Nos. 3 and 4, .were treated by the same procedure, thusaffording respectively: 19,19-diflUOI0-17uvinyl-M-androstene-Sfl,173-diol (Cpd. No. 7) and 19,19- difluoro-l7a-ethynylA-an-drostene-3/3,l7/i-diol (Cpd. No. 8).

Example IV A solution of l g. of 19,19-difiuoro-A -androstene-313,17fl-diol (Cpd. No. 5) in cc. of toluene and 20 cc. of cyclohexanonewas dried by distilling off 10 cc.

of the solvent. A solution of 1 g. of aluminum iso-propoxide dissolvedin 7 cc. of anhydrous toluene was then added and the mixture wasrefluxed for 45 minutes; 4 cc. of acetic acid were added and thesolvents removed by steam distillation. The product was extractedseveral times with ethyl acetate and the organic extracts washed with 5%hydrochloric acid solution, water, sodium carbonate solution and wateruntil neutral, dried over anhydrous sodium sulfate and evaporated todryness. Crystallization from acetone-hexane afforded 19,19-difluoro-A-androstene-3,17-dione (Cpd. No. 9).

By the same procedure the compounds Nos. 6, 7 and 8 were respectivelyconverted into: 19,19-difluoro-l7amethyl-A -androstene-l7/3-ol-3-one(Cpd. No. 10), 19,19- difluoro-17a-viuyl-A -androstene-17,8-01-3-one(Cpd. No. 11) and 19,19-difiuoro-17a-ethynyl-A -androstene-1713-01-3-one (Cpd. No. 12).

Example V A solution of 2 g. of sodium borohydride in 30 cc. of methanolwas added with stirring to a solution of 2 g. of Compound No. 9 in 40cc. of tetrahydrofuran. The mixture was kept at room temperatureovernight, the excess reagent was decomposedby addition of acetic acid,the resulting solution concentrated to small volume in vacuo and dilutedwith water. The product was extracted with ethyl acetate, the extractwashed with water, dried and evaporated. Crystallization of the solidfrom acetonehexane gave 19,l9-difluoro-A -androstene 3,8,175 diol (Cpd.No. 13).

A mixture of 1 g. of the latter product in cc. of dioxane, and 1.1 molarequivalents of 2,3-dichloro, 5,6- dicyano, 1,4-benzoquinoue was kept atroom temperature for 3 hours. The hydroquinone formed during thereaction was filtered. off, and the filtrate evaporated to drymess. Theresidue was dissolved in acetone and filtered through 20 g. of alumina.Crystallization from acetonehexane gave 19,19 difluoro Aandrosten-l7B-ol-3-one (Cpd. No. 14).

Example VI A solution of 1 g. of Compound No. 14 in 20 cc. ofdioxane-ether (1:1) was added in a steady stream to a solution of'0.1 g.of lithium in 100 cc. of anhydrous liquid ammonia with good stirring. Atthe end of the addition the .blue color was discharged by the additionof 5 g. of ammonium chloride and the ammonia was allowed to evaporate.The product was extracted with ether, washed with water, dried and theether evaporated to afford a gum which was adsorbed from 100 cc. ofbenzene onto 50 g. of alumina. Elution with benzene-ether afforded aproduct which upon recrystallization from actonehexane gave19,19-difluoro-androstane-17fl-ol-3-one (Cpd. No. 15).

The compounds Nos. 10, 11 and 12 were treated by the same procedure,thus affording respectively:19,19-difiuoro-l7a-methyl-androstane-17/3-ol-3-one (Cpd. N0. 16), 19,19difiuoro-l7a-vinyl-androstane-17fi-ol-3-one (Cpd. No. 17) and19,19-difluoro-17a-ethynyl-androstane-17(3- ol-3-one (Cpd. No. 18).

Example VII To a solution of 3 g. of 19,19-difluoroandrostane-17B-ol-3-one (Cpd. No. 15) in 60 cc. of anhydrous benzene was added 3 cc. ofethyl formate and 1.3 g. of sodium hydride, suspended in mineral oilwhile cooling and stirring under an atmosphere of nitrogen. The mixturewas stirred for 24 hours at room temperature, hexane was added untilcomplete precipitation, the solid was collected and dried under vacuum.The crude material was suspended in aqueous hydrochloric acid andstirred at room temperature for half an hour. The precipitate wascollected, washed with water and dried. Recrystallization from methylenechloride-hexane gave2-hydroxymethylenel9,l9-difluoro-androstane-17,B-ol-3-one (Cpd. No. 19).

The compounds Nos. 16, 17 and 18 were treated'by the above method toproduce respectively:

Cpd. No.:

20. 2-hydroxymethylene-l9,l9-difluoro-17-methylandrostane-17fi-ol-3-one. 21. 2-hydroxymethylenel 9, l9-difiuoro- 17ot-vinylandrostane-17B-ol-3-one. 22.2-hydroxymethylene-19,19-difluoro-l7a-ethynylandrostane-17/3-ol-3-one.

Example VIII tallization from aetone-hexane afiorded 2-methoxymethylene19,19 difluoro-androstane-17fi-ol-3-one (Cpd. No. 23).

The compounds Nos. 20, 21 and 22 were treated by the same procedure,thus giving respectively:

Cpd. No.2

24. 2-methoxymethylene-19,19-difluoro-17a-methylandrostane-17B-ol-3-one.25. 2-methoxymethylene-19,19-difiuoro-17a-vinylandrostane-l7fl-ol-3-one.26.2-methoxymethylene-19,19-difluoro-17a-ethynylandrostane-l7fi-ol-3-one.

2 Example IX A solution of 1 g. of sodium borohydride in 3 cc. of waterwas added to an ice-cooled solution of 1 g. of 2- m'ethoxymethylene19,19-difluoro androstan-l7p-ol-3- one (Cpd. No. 23) in cc. of methanoland the mixture was allowed to stand for 16 hours at room tem perature.The excess reagent was decomposed by addition of acetic acid; thesolution was then acidified with 1 cc. of concentrated hydrochloric acidand left at room temperature for 10 minutes. It was thereafter concentrated to small volume in vacuo and diluted with water. The product wasextracted with ethyl acetate, the extract was washed with water, driedand evaporated. The solid residue was purified by crystallization fromacetonehexane to give 2-formyl-l9,l9-difluoro-A -androstene-- ol (Cpd.No. 27).

following the above procedure the compounds Nos. 24, 25 and 26 wererespectively converted into:

Cpd. No.:

28. 2-formyl-l9,19 difluoro-17a methyI-A -androstene-17fl-ol.

29. 2-formyl 19,19 difl-uoro-17u-vinyl-A -androstene-l7/3-ol.

30. 2-fonmyl 19,19 difluoro-17a-ethynyl-A -androstene-17/3-ol.

Example X A solution of 3 g. of 2-formyl-19,l9-difluoro-A-androstene-l7/3-ol (Cpd. No. 27) in 70 cc. of benzene was concentratedto a volume of 50 cc. in order to remove moisture. Thereafter, 1 cc. ofpyridine and 2 g. of N,O-bis trifiuoromethyl hydroxylamine were added,and the mixture was refluxed for 4 hours. The solution was poured intowater, extracted with ethyl acetate, the extract washed with water,dried over sodium sulfate and evaporated to dryness. Upon chromatographyon 100 g. of alumina there was produced: 2-cyano-19,19-difluoro-Aandrostene-17B-ol (Cpd. No. 31).

7 The compounds Nos.' 28, 29 and 30 were treated according to the abovetechnique, thus yielding respectively:

Cpd. No.:

32. 2-cyano 19,19-difiuoro 17u-rnethy1-A -androstene-17p-ol.

33. 2-cyano 19,19- -difluoro 17a-vinyl-A -androstene-17,B-ol.

34, Z-cyano 19,19 difluoro 17u-ethynyl-A -androstene-17/3-ol.

Example XI A mixture of l g. of 19,l9-difiuoro-A -androstene-17 8-ol-3-one (Cpd. No. 14) 4 cc. of pyridine and 2 cc. of acetic anhydridewas kept at room temperature overnight,-

poured into ice water, the formed precipitate was filtered, washed withwater and dried. Crystallization from acetonehexane gave19,l9-difluoro-A -androsten-l7fl-ol-3-one acetate (Cpd. No. 35).

Following the same procedure there were treated the compounds Nos. 15,19, 23, 27 and 31 yielding respectively:

The starting compounds of the foregoing example, were treated inaccordance with that example, except that acetic anhydride wassubstituted by caproic anhydride and by enanthic anhydride, thusaffording respectively the corresponding caproates and enanthates ofsaid starting compounds. Example XIII To a solution of 5 g. of19,19-difluoro-17a-methyl-A androstene-17/3-ol-3-one (Cpd. No. in 100cc. of anhydrous benzene there were added 1 g. of p-toluene-sul-- fonicacid and 10 cc,. of acetic anhydride and the mixture was allowed tostand for 24 hours at room temperature, poured into ice and water, andthe resulting mixture stirred to effect hydrolysis of the excessanhydride. The benzene layer was separated and washed with 10% sodiumcarbonate solution and water. Drying, evaporation and crystallization ofthe residue from-ether-hexane produced 19,19-difluoro-17a-m'ethyl-A-androstene-17fi-ol 3-0ne acetate (Cpd. No. 41).

The compounds Nos. 11, 12, 16, 17, 18, 20, 21, 22, 24, 25, 26, 28, 29,30, 32, 33 and 34 were treated by the above procedure, to giverespectively:

45. 19, l9-difiuoro-l7a-vinyl-androstane- 17 6-01-3 -0nc acetate.

46. 19,l9-difluoro-17u-ethynyl-androstane-17,8-01 3,-

one acetate.

47. 2-acetoxymethylene-19,l9 difiuoro-l7a methylandrostane-17fl-ol-3-oneacetate.

48. 2-acetoxymethylene-19,19-difluoro 170a vinylandrostane-l7fl-ol-3r'one acetate.

8 49. 2-acetoxymethylene-19,19-difluoro-l7aethynylandrostane-l7fi-ol-3-one acetate. 50.Z-methoxymethylene-19,19-difiuoro-17a-methylandrostane-l7fl-ol-3 oneacetate. 51. 2-rnethoxymethylene-19,19-difluoro-17avinylandrostane-17fl-ol-3-one acetate. 52.2-methoxymethylene-l9,l9-difiuoro-17ot ethynylandrostane-17,6-01-3-oneacetate.

53. 2-formyl-l9,l9-difluoro-l7a-rnethyl A androstene-17fi-ol acetate.

5 4. 2-forrnyll 9, l9-difluoro- 17 a-vinyl-M-androstene- 1713-01acetate.

55. 2-formyl-19,l9-difluoro-l7ot-ethynyl-A androstene-17B-ol acetate.

56. 2-cyano-19,19-difiuoro-17a-methyl-A -androstene- -01 acetate. 7 57.2-cyano-19,19-difluoro-l7ouvi-nyl-A androstene- 17,6-01 acetate. 58.2-cyano-l9,l9-difiuoro-l7a-ethynyl A androstene-17fl-ol acetate.

EXAMPLE XIV The starting compounds of the preceding example were treatedin accordance with that example, except that acetic anhydride wassubstituted by caproic anhydride and by undecenoic anhydride, thusatfording respectively the corresponding caproates and undecenoates ofsaid starting compounds.

We claim:

1. A compound of th following formula:

FzHC p zox/l wherein R and R are selected from the group consisting ofhydrogen and a hydrocarbon carboxylic acyl group of -less than 12 carbonatoms; and R is a member of the group consisting of hydrogen, loweralkyl, lower alkenyl and lower alkynyl.

2. 19,19-difluoro-A -androstene-3B,17fl-diol. 3.17a-methyl-l9,19-difluo1'o-A -androstene-3{3, l7fl-diol. 4.l7a-vinyl-19,l9-difluoro-A -androstene-3[3,17,8-diol.

6. A compound of the following formula:

IOR

wherein R is selected from the group consisting of hydrogen, and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is amember of the group consisting of hydrogen, lower alkyl, lower alkenyland lower alkynyl; and Z is selected from the group consisting of adouble bond and a saturated linkage between C-4 and C5.

' 7. l9,l9-difiuoro-A -androsten-17,8-ol-3-one.

8. l7a-methyl-l9,19-difluoro-A -androsten-17fl-o1-3-one. 9.17a-vinyl-l9,l9-difluoro-A -androsten-17flol-3-one. 10.l7a-ethynyl-l9,l9-difiuoro-A -androsten-173-01 3- one,

11. A compound of the following formulaz wherein R is selected from thegroup consisting of hydrogen, and a hydrocarbon carboxyli-c acyl groupof less than 12 carbon atoms; R is a member of the group consisting ofhydrogen, lower alky-l, lower alkenyl and lower alkynyl; and R isselected from the group consisting of hydrogen, lower alkyl and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms.

12. 2-hydroxymethylene-19,19-difluoro-androstan 17/3- ol-3-one.

13. 2-hydroxymethylene-19,19-difiuoro 17a methylandrostan-l7 3-ol-3-one.

14. 2-hydroxymethylene-19,l9-difiuoro 17a vinylandrostan-17fl-ol-3-one.t

15. 2-hydroxymethylene-19,19-difiu0ro-17a ethynylandrostan-17B-ol-3-one;

16. A compound of the following formula:

OR i ii OHCH/\ vs 18. Z-formyl-19,19-difiu0ro-17or-methyl-A androsten--19. A compound of the following formula:

wherein R is selected from .the group consisting of hydrogen, and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R is-a member of the group consisting of hydrogen, lower alkyl, loweralkenyl and lower alkynyl.

20. 2-cyano-19,19-difluoro-A -androsten-1713-01.

21. Z-cyano-19,19-diflu0ro-17m-methyl-A androsten- 175-01. 7

References Cited by the Examiner UNITED STATES PATENTS 8/1963 Bowers260397.4

8/1963 Bowers 26O-397.4

LEWIS GOTTS, Primary Examiner.

1. A COMPOUND OF THE FOLLOWING FORMULA: